Safety Issue Puts Daclizumab in Doubt for MS

by John Gever John Gever,Senior Editor, MedPage Today
October 15, 2012

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Daclizumab, a biologic drug targeting the interleukin-2 pathway, showed sustained efficacy in the second year of a phase II trial in multiple sclerosis, but serious autoimmune issues also emerged.

Note that one patient died from autoimmune hepatitis and that hepatic monitoring in the daclizumab clinical program was enhanced after the potential for such effects was recognized.

LYON, France -- Daclizumab, a biologic drug targeting the interleukin-2 pathway, showed sustained efficacy in the second year of a phase II trial in multiple sclerosis, but serious autoimmune issues also emerged, researchers said here.

In a randomized extension study of high-yield process daclizumab called SELECTION, efficacy according to most measures was maintained or even increased in relapsing-remitting MS patients who had participated in the one-year SELECT trial, according to Gavin Giovannoni, MD, of Queen Mary University in London.

But one patient died from autoimmune hepatitis and two others developed autoimmune conditions affecting vital organs, he reported at a late-breaking abstract session at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.

Hepatic monitoring in the daclizumab clinical program was stepped up after the potential for such effects was recognized, Giovannoni said. Nevertheless, other researchers suggested that the problem was serious enough to jeopardize the drug's future in MS.

Daclizumab binds to the CD25 receptor protein, thereby preventing T cells from taking in IL-2. The resulting change in immune system activity is believed to decrease the autoimmune attack on nerve tissues that characterizes MS.

In the original randomized SELECT trial, annualized relapse rates after one year of treatment were cut by 50% with either of two doses of daclizumab versus placebo, and other outcome measures such as MRI lesion burden and disability progression were also significantly better with the drug.

At the end of SELECT, patients were offered participation in the one-year extension study, in which those originally taking placebo were re-randomized to the same two doses used in the original trial (150 or 300 mg, by subcutaneous injection every 4 weeks).

Patients in the SELECT active drug arms were also re-randomized to receive either continuous treatment with the same dose as in the original trial, or to a 24-week washout period followed by resumption of the original dose for 24 weeks.

The purpose, Giovannoni explained, was threefold: to confirm the drug's efficacy in the original placebo group, to examine the durability of its effects with continuous treatment, and to see whether it would retain its efficacy when restarted after treatment interruption.

Of 621 patients completing SELECT, 517 chose to participate in SELECTION, with 92% remaining through the full year.

Patients in the initial placebo group had shown a mean annualized relapse rate of 0.434 in SELECT. When they switched to daclizumab, relapse rates fell to 0.179 (95% CI 1.23 to 0.261) in pooled data on both dosages, a decline of 59%.

Disability progression in those patients was also reduced. A total of 17 patients in the placebo group during SELECT developed 3-month progression; in the extension phase, only seven of the former placebo patients showed such progression (P=0.033).

New or enlarging T2 MRI lesions declined by 74% after switching to active treatment, and new gadolinium-enhancing T1 lesions decreased 86%, Giovannoni said (P not reported).

In patients continuously treated with daclizumab, annualized relapse rates and the slowing of disability progression seen in SELECT was maintained in SELECTION, on the basis of pooled data in both dosage groups.

In the patients randomized to the 24-week daclizumab washout, gadolinium-enhancing lesion numbers rebounded to about triple the level seen at the end of SELECT, although they remained lower than at baseline.

But at the end of SELECTION, when these patients had resumed daclizumab treatment for 6 months, mean lesion counts fell back to levels similar to those at the end of SELECT.

Giovannoni also reported that CD56bright natural killer cell counts, a laboratory measure of daclizumab treatment, had risen roughly 10-fold from baseline during SELECT but leveled off in continuously treated patients in the extension.

He said that was an indication that maximal drug effect may not be achieved until the second year of treatment.

As in most MS drug trials, adverse events were common. But serious adverse events excluding relapses were not, with rates ranging from 5% to 8% in each treatment arm.

Among the 517 patients treated in SELECTION, these included 13 serious infections, six skin events, eight cases of liver enzyme elevations beyond five times the upper limit of normal, one cancer, and the three cases of autoimmune attacks.

Mark Freedman, MD, of the University of Ottawa, who was not involved in SELECT or SELECTION, told MedPage Today that the autoimmune issue could make the drug unapprovable, despite what he said was "a very potent [efficacy] signal without too much worrisome problems" in the initial phase.

He noted that the SELECT-SELECTION program had alleviated one safety concern for the drug, arising from its mechanism of action.

Because the drug targets the IL-2 pathway, he explained, some researchers worried that it might actually exacerbate rather than relieve MS. "A lot of cells use IL-2 to move, including regulatory T cells," Freedman said. The strong efficacy benefit clearly indicates that those concerns were groundless.

But, he added, "I'm a little discouraged by the emerging autoimmune abnormalities -- and they're not single organ."

He acknowledged that the developers of another investigational MS drug, alemtuzumab (Lemtrada), have not been discouraged by its propensity to induce autoimmune thyroid disease.

But that's a less serious condition than the hepatic and renal autoimmune conditions seen in the daclizumab study, said Freedman, who is an investigator in an ongoing phase III trial of the drug.